The broad, long-term objectives of this proposal are to develop improved strategies for mechanical ventilation of the non-uniform lung and for assessing non-uniform lung dysfunction. This proposal is motivated by the recognition that, in the physiological range of respiratory frequencies, lung tissue visco-elasticity has a major contribution to pulmonary impedance and that elastic and dissipative tissue forces are not independent, but appear to be coupled so that interventions that affect one also tend to affect the other in approximately equal proportion. A potential physiological significance of these observations is that changes in tissue visco-elastic properties could be a major factor in controlling regional ventilation while maintaining synchronous lung expansion by modulating regional elastance without changing regional time constants. This possibility sheds new light on earlier speculations that distal airways smooth muscle constriction could be part of a homeostatic mechanism to maintain uniform matching of V/Q. The Specific Aims of this project are: 1) Test the appropriateness of a non-linear model of smooth muscle mechanics to describe the regional mechanical changes in lung tissue properties caused by peripheral constriction. 2) Identify and assess the physiological relevance of regional changes in lung tissue visco-elasticity and 3) Apply these concepts to evaluate lung mechanics and regional gas transport in a non- uniform system, specifically that resulting from unilateral lung transplant. The project will study: 1) The non-linear visco-elastic behavior of lung tissue and its alteration during vagal stimulation or histamine aerosol. 2) The regional chest wall-lung interdependence. 3) The regional effects of pulmonary perfusion, PO2, and PCO2 on airway and tissue properties and ventilation distribution. 4) The changes in regional lung mechanics after unilateral lung transplantation. The common approach consists of formulating simple mechanical models and performing experiments to quantitatively evaluate the different components of the models. The methods include classical respiratory mechanics techniques, such as forced oscillations and flow interruption, and recently developed positron imaging techniques for quantitative regional assessment of dynamic lung volumes and gas transport, allowing regional lung mechanics to be characterized non- invasively. The proposed experiments are relevant to a broad range of non- uniform respiratory ailments and they are particularly pertinent to the management of the unilaterally transplanted lung. Taking advantage of concurrent surgical research on lung transplantation, experiments have been designed to quantitate postoperative lung function, and regional changes resulting from factors such as graft rejection, size mismatch and growth, and lung preservation techniques.